This invention relates to treatment and curing of neurological diseases in animals and humans, and particularly to neurological diseases that may be caused by fungus, yeast or prion proteins
Diseases of the class relating to spongiform encephalopathies, which include xe2x80x9cmad cowxe2x80x9d disease and scrapie in animals, and Creutzfeld-Jakob disease (CJD) and possibly some types of Alzheimer""s disease in humans, are transmissible conditions affecting nervous systems of mammals, birds and reptiles. Commonly infected species include man, sheep, goats, cows, deer, elk, mink, cats, mice, chickens, and others. In these diseases, and after an incubation period, neurological dysfunctions and death occur due to deterioration of nervous tissue. In some of these diseases, amyloid plaques form in the brain, particularly in Alzheimer""s-type diseases, these plaques in some instances being laced with protein fibrils that may resemble a mycelial phase of fungal origin. In other instances, localized areas of neurons in the brain become riddled with lesions and neurons having vacuoles such as those found in certain yeasts. In prion diseases, and from a histochemical standpoint, an infective form of a glycosyl-phosphatidylinositol (GPI)-anchored cell surface prion protein (PrPc) possessing a beta sheet configuration enters neurons of the brain of the host animal and is converted to an aberrant isoform (PrPSc). In this conversion to an infectious form, it has been found that normal GPI proteins, which are found on nerve cells and which possess an alpha helical structure, are converted to the infectious beta sheet configuration by contact with an infectious form of the prion. During replication, the PrPSc beta configuration of the prion is believed to cause vacuolization, swelling and degeneration of neuronal cell bodies and grey matter neuropils, causing lesions and vacuoles in brain tissue of the host animal characteristic of spongiform encephalopathy.
Other neurological diseases in humans such as multiple sclerosis, Parkinson""s disease, Huntington""s disease, amyotrophic lateral sclerosis, Canavans disease, adreno leukodystrophy, metachromic leukodystrophy, Krabbe disease, Fabry disease, Neimann-Pick disease, Pelizaeus-Merzbacher disease and Guillain-Barre syndrome are believed by Applicant to be caused by yeast, fungi or prion protein-based yeast or fungal structures. In mammals in general, Applicant believes neurological diseases such as Rottweiler leukoencephalomyelopathy, polyradiculoneuritis (coon hound paralysis), degenerative myelopathy in German shepherds, transmissible spongiform encephalopathy and shaker puppies may be caused by yeast, fungi, or prions based upon yeast or fungal structures.
At present, there is no known cure for these diseases. An anti-fungal drug, amphoteracin-b, which is a growth inhibitor, has prolonged the incubation time of scrapie in hamsters, suggesting a fungal, yeast or prion protein-based cause of these diseases. However, this drug is ineffective in ultimately preventing onset of neurological symptoms or halting neuronal destruction and subsequent death of the animal.
Another compound, Congo Red, a stain used in pathological studies to highlight or define amyloid structures in tissues, has been tested as a therapeutic agent. Here, it has been proposed that Congo Red may reduce the number of protein fibrils found in amyloid structures. Additionally, Congo Red may inhibit yeast cell wall production, in turn reducing capacity of the infecting yeast to reproduce. However, Congo Red is not seen as a curative agent for spongiform encephalopathies or other neurological diseases.
Dapsone, an anti-inflammatory drug, may delay clinical signs of CJD but does not delay formation of plaques in Alzheimer-type diseases. Also, Dapsone may hinder macrophage processing of the CJD agent. As one possible infection route, biting insects such as sheep keds, hay mites, ticks and others have been implicated as naturally occurring vectors for transmission of fungal, yeast or prion diseases. Practices of feeding domestic animals fodder containing animal protein (offal containing neurological tissue) have been studied as well, and are correlated with transmission of certain prion diseases such as mad cow disease and scrapie. Here, although offal is cooked or rendered, killing bacteria and most viruses, prions are known to withstand temperatures of up to 600 degrees Fahrenheit or so.
Lyme disease, a tick-borne disease caused by the bacteria Borrelia burgdorferi, is conventionally treated with antibiotics. However, a large percentage of patients diagnosed with Lyme disease have later shown forms of dementia similar if not the same as the dementia demonstrated by victims of Alzheimer""s disease. While the bacteria Borrelia burgdorferi is the causative agent of Lyme disease, the cause of subsequent dementia after resolution of the Lyme disease has not been determined. Here, Applicant proposes that a single tick with an attachment time of about 18 hours or so, the time it takes for an attached tick to become engorged, could serve as a vector for fungal, yeast or prion diseases that are manifested months to years after initial infection by the tick vector.
In one study of tick haemolymph analysis, valine, inositol and glucose were appreciably higher in concentration than other amino acids and sugars, valine, inositol and glucose also being found in yeasts and fungi, suggesting that ticks and other biting insects may harbor infectious yeasts and/or fungi. Additionally, valine, inositol and glucose are found in prion proteins, also suggesting a link between yeast, fungi and prions. Further, in mammals in general including humans, fungi and yeast are common skin-dwelling organisms. Ticks often migrate to the head and neck region, which is also an area proximate an abundance of neurological tissue rich in sugars such as glucose, a preferred food source of yeasts. As such, yeast or fungal cells may be introduced at the head or neck region of an animal by ticks or other biting insects.
One possible causative yeast suggested by Applicant, Saccharomyces cerevesiae (SC), generally regarded to be normal flora to both human and animals, and commonly used in brewing and baking, bears significant similarities to prions. Both prions and SC are resistant to formaldehyde, are resistant to temperature extremes, have glycosyl-phosphatidylinosital (GPI) protein surface anchors, and have glucose and mannose as surface sugar components. Glucose and mannose as surface sugars may aid in sc ingestion by host macrophages. Here, it may happen that a macrophage does not kill the ingested yeast, but inadvertently transports the yeast to a part of the body where the yeast gains access to the central nervous system of the host. It may also happen that some process within the macrophage initially converts the yeast into a prion protein.
Significantly, GPI protein surface anchors are also found on the surface of mammalian nerve cells. SC can also synthesize methionine and valine, it being noted that in the infective form of many prions that have been studied, methionine or valine is substituted for another amino acid at codon 129 of the prion protein. Further, SC has receptor sites for hormones such as insulin, human chorionogonadotropin and estradiol. Another feature of SC is the production of trehalose, a disaccharide composed of two glucose molecules. In general, trehalose provides thermoprotection to the yeast cells, and further provides thermoprotection to proteins of non-yeast origin, such as bovine serum albumin. Trehalose is also used to protect mouse embryos from dehydration and during freezing, and is found in tick haemolymph, another suggestion that ticks may harbor yeast and/or fungi that may infect mammals. Further, ceramide, a protein manufactured by cells in the central nervous system of mammals, may be used by SC to manufacture trehalose. Since SC manufactures trehalose, it may be that trehalose is manufactured by prion proteins of SC or other yeast or fungal origin, thus providing the observed thermal resistance of prions.